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Diseases of the circulation (hypertension, heart failure, coronary vascular disease and stroke) are some of the biggest killers in Western society. We aim to improve understanding of the effects of disease on blood vessel function and to produce strategies for prevention and alleviation of organ damage arising from blood vessel malfunction. We are approaching this problem by elucidating the physiological, cellular and molecular mechanisms of drug action on the vasculature and its endothelial lining. |
Mechanisms of vasodilator action
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For a number of years, we have studied actions of vasodilators (e.g. nitric oxide, adenosine, levcromakalim) and vasoconstrictors (e.g. endothelin, a-adrenoceptor agonists) on resistance vessels. Recent work has included study of endothelium-derived hyperpolarising factor (EDHF) and its sensitivity to K+ channel blockers [1,2] and we have also elucidated some interactions between K+ channel vasodilator mechanisms (e.g. levcromakalim, EDHF) and those dependent on nitric oxide/cyclic GMP [3, 4] as well as investigated the membrane potential changes evoked by vasodilators (such as K+ channel openers [5] and purinoceptor agonists [6]) in endothelial cells in situ. |
| Dr Hiley in the Lab
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| Vanessa Ho, who has recently completed a PhD studying the vascular actions of cannabinoids, preparing vessels for mounting in the myograph
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| Hammit Mistry, a recent graduate student, working on the electrophysiology rig
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Vascular pharmacology of cannabinoids
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Since 1997 we have had an interest in the cardiovascular actions of cannabinoids, starting with an investigation of the endocannabinoid, anandamide, as a potential candidate for EDHF [2].
We showed that anandamide and the responses evoked by EDHF-releasing agents, carbachol and A23187, were differentially sensitive to inhibition of K+ channels and that the K+ channels concerned were on the endothelium rather than the vascular smooth muscle. We have since shown that the responses to cannabinoid agonists in rat blood vessels (the mesenteric [7,8] and the coronary arteries [9,10]) do not seem to be mediated through the classical CB1 and CB2 receptors.
Current work is intended to characterise the receptor mediating these responses and, in collaboration of Dr Will Ford, also the cardioprotective effects of the endocannabinoids. |
| Margaret Hickman, our senior technician, working on one of the wire myograph systems
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The laboratory uses perfusion of vascular beds in vitro (particularly the coronary and mesenteric vasculature), wire- and video myographs, electrophysiology and tissue culture. Active collaborations are with Dr Alain Vuylsteke, Consultant Anaesthetist, Papworth Hospital, Cambridgeshire (concerning vascular actions of blood substitutes [11]) and Dr Will Ford (concerning the cardioprotective effects of cannabinoids) of the Welsh School of Pharmacy, Cardiff.
- McCulloch, A.I., Bottrill, F.E., Randall, M.D. & Hiley, C.R. (1997). Characterization and modulation of EDHF-mediated relaxations in the rat isolated superior mesenteric arterial bed. Br. J. Pharmacol. 120: 1431-1438.
- White, R. & Hiley, C.R. (1997). A comparison of EDHF-mediated and anandamide-induced relaxations in the rat isolated mesenteric artery. Br. J. Pharmacol. 122: 1573-1584.
- White, R. & Hiley, C.R. (1998). Effects of K+ channel openers on relaxations to nitric oxide and endothelium-derived hyperpolarizing factor in rat mesenteric artery. Eur. J. Pharmacol. 35741-51.
- White, R. & Hiley, C.R. (1998). Modulation of relaxation to levcromakalim by S-nitroso-N-acetylpenicillamine (SNAP) and 8-bromo cyclic GMP in the rat isolated mesenteric artery. Br. J. Pharmacol. 124: 1219-1226.
- White, R. & Hiley, C.R. (2000). Hyperpolarisation of rat mesenteric endothelial cells by ATP-sensitive K+ channel openers. Eur. J. Pharmacol. 397. 279-290.
- Mistry, H., Gitlin, J.M., Mitchell, J.A. & Hiley, C.R. (2003). Endothelium-dependent relaxation and endothelial hyperpolarization by P2Y agonists in rat isolated mesenteric artery. Br. J. Pharmacol. 139: 661-671.
- White, R. & Hiley, C.R. (1998). The actions of some cannabinoid receptor ligands in the rat isolated mesenteric artery. Br. J. Pharmacol. 125: 533-541.
- Ho, W-S.V. & Hiley, C.R. (2003). Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. Br. J. Pharmacol. 138: 1320-1332.
- White, R., Ho, W-S.V., Bottrill, F.E., Ford, W.R. & Hiley, C.R. (2001). Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br. J. Pharmacol. 134: 921-929.
- Ford, W.R., Honan, S.A., White, R. & Hiley, C.R. (2002). Evidence of a novel site mediating anandamide-induced negative inotropic and coronary vasodilatator responses in rat isolated hearts. Br. J. Pharmacol. 135: 1191-1198.
- Vuylsteke, A., Davidson, H.J., Ho, W.-S.V., Ritchie, A.J., Callingham, B.A., White, R. & Hiley, C.R. (2001). Effect of the blood substitute diaspirin cross-linked haemoglobin (DCLHb) in rat mesenteric and human radial collateral arteries. J. Cardiovasc Pharmacol. 37: 394-405.
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References